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Discovery of selective inhibitors of fibroblast growth factor receptor 1 kinase with potent anti‐human lung carcinoma activity
Author(s) -
Liang Guang,
Wang Yi,
Zhou Huiping,
Li Xiaokun
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.601.6
Subject(s) - fibroblast growth factor receptor , fibroblast growth factor receptor 1 , cancer research , protein kinase b , mapk/erk pathway , phosphorylation , tyrosine kinase , chemistry , kinase , fibroblast growth factor , receptor tyrosine kinase , signal transduction , microbiology and biotechnology , biology , receptor , biochemistry
The fibroblast growth factor receptor (FGFR) tyrosine kinases represent promising therapeutic targets in a number of cancers. In this study, we developed two potent and selective inhibitors of FGFR1, which we named A114 and A117. We demonstrated that the inhibitors potently inhibit the FGFR1 kinase activity in a non‐ATP competitive manner through caliper mobility shift assay. The docking simulation of indicated compound with FGFR1 protein reveals that the 4‐substituted groups of phenyl ring may occupy the hydrophobic front region, which is consisted of hinge residues (Ile 651, Lys 655, Val 664, Met 667 and Tyr 677). Furthermore, we proved that the inhibitors potently inhibit the growth of numerous FGFR‐dependent cancer cell lines via inactivating the phosphorylation of FGFR1, leading to a decrease in phosphorylation of Akt and ERK signaling. The inhibitory effect in both the FGFR and MAPK signaling pathway finally leads to the decrease in cell viability, cell cycle arrest, and apoptosis in non‐small cell lung cancer H460 cells both in vitro and in vivo. Together, these results suggest the anti‐cancer potential of novel curcumin analogs for the prevention and treatment of FGFR‐depending cancers. The work was supported by grants from the National Natural Science Foundation of China (81173083 & 21102106).